The effect of innate immunity on B cell tolerance

Summary

Principal Investigator: Thereza Imanishi-Kari
Abstract: DESCRIPTION (provided by applicant): Recent evidence increasingly points to the importance of antibodies specific for RNA antigens in the pathogenesis of SLE. Using a novel mouse model in which RNA-specific B cells are generated and easily tracked, and in which clinical SLE pathologies are recapitulated, new and critical information on the pathogenesis of SLE will be obtained. The mouse line to be used, 564Igi, was generated in our laboratory and has already made an important contribution to the emerging understanding of the role played by TLRs, in particular TLR7, in the development of SLE. In this system, on the non-autoimmune C57BL/6 background, most RNA-reactive B cells undergo receptor editing, while those that retain their RNA-specificity become anergic by multiple criteria. Yet class-switched pathogenic autoantibodies are produced by a T-independent, but TLR7-dependent mechanism. Thus, either anergic RNA-specific IgM+ B cells are capable of activation and differentiation into IgG producing cells in response to self-antigen, or a subpopulation of these cells is able to evade anergy, namely those that have undergone CSR in the bone marrow during B cell development in response to self-antigen encounter. In the current proposal, these two models will be tested in detail. In either case, the signals required for differentiation into antibody producing cells and the extent to which there are contributions from non-B cells will be determined. Finally, the effect of autoimmune-prone backgrounds on the regulation of RNA-specific B cells in the 564Igi system will be studied. These experiments will help unravel the mechanisms by which RNA-specific B cells become activated and produce pathogenic autoantibodies in SLE.
Funding Period: 2010-07-02 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. pmc Expression of an anti-RNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN-I expression
    Jin Hwan Han
    Graduate Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA
    Eur J Immunol 44:215-26. 2014
  2. pmc Dosage of X-linked Toll-like receptor 8 determines gender differences in the development of systemic lupus erythematosus
    Benjamin R Umiker
    Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA
    Eur J Immunol 44:1503-16. 2014

Research Grants

Detail Information

Publications2

  1. pmc Expression of an anti-RNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN-I expression
    Jin Hwan Han
    Graduate Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA
    Eur J Immunol 44:215-26. 2014
    ....
  2. pmc Dosage of X-linked Toll-like receptor 8 determines gender differences in the development of systemic lupus erythematosus
    Benjamin R Umiker
    Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA
    Eur J Immunol 44:1503-16. 2014
    ..Collectively, we suggest that individual TLRs play unique roles in the pathogenesis of systemic lupus erythematosus, suggesting new targets for treatment. ..

Research Grants30

  1. Philadelphia Autoimmunity Center of Excellence
    A M Rostami; Fiscal Year: 2013
    ..The Clinical Component proposes novel clinical trial concepts and studies to understand the mechanisms of action of the therapeutics being tested. As such, they are an integral part of this ACE. ..
  2. Citrullinated Antigens Bridge Innate and Adaptive Immunity in RA
    Jeremy Sokolove; Fiscal Year: 2013
    ....
  3. Mechanisms of B-Cell Tolerance in a Mouse Model of Lupus
    Allison Sang; Fiscal Year: 2013
    ..A thorough understanding of B-cell tolerance and the breakdown that occurs in SLE will provide targets for future B-cell therapies. ..
  4. Modulation of B cell tolerance checkpoints by distinct Ras/Erk Pathways
    Andre Limnander; Fiscal Year: 2013
    ....
  5. Autoimmunity Center of Excellence (ACE) at Stanford
    CHARLES GARRISON FATHMAN; Fiscal Year: 2013
    ..The Stanford ACE proposes clinical research projects that encompass three different autoimmune diseases (SSc, psoriatic arthritis and SJIA), and proposes to study the MoA of therapeutics for preventing or treating different Al diseases. ..
  6. Immune Mechanisms That Control Ectromelia Virus Infection
    Luis J Sigal; Fiscal Year: 2013
    ..The results from this Project will provide a comprehensive picture of the innate response to a peripheral virus infection. ..
  7. Identification of Specific Roles for Ets-1 in B Cell Tolerance
    Lee Ann Garrett-Sinha; Fiscal Year: 2013
    ....
  8. B Cell Development Defects in Murine Lupus
    Laurence Morel; Fiscal Year: 2013
    ..The results from these studies will provide a better understanding of the defining features of autoreactive B cells and will help to target therapies toward these autoreactive B cells. ..
  9. DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM
    Christopher B Newgard; Fiscal Year: 2013
    ..abstract_text> ..
  10. Lupus and the inhibitory dual receptor hypothesis
    GREGG JOSHUA SILVERMAN; Fiscal Year: 2013
    ..We anticipate that these studies will reveal new insights into immune regulation and autoimmune pathogenesis, and provide the essential bridge from basic studies to the development of a new therapeutic approach to the treatment of SLE. ..
  11. Effects of miR-21 and miR-155 inhibition in SLE
    Marianthi Kiriakidou; Fiscal Year: 2013
    ..To our knowledge HITS-CLIP has not been previously performed in SLE and the combined results of HITS-CLIP and RNAseq will offer a panoramic view of all genes directly regulated by miRNAs in cells of the immune system in mouse lupus. ..